Spinal opioid analgesia by application of opioid agonists into the intrathecal or epidural space has played a major role in the control of pain during the past decade. It has the major advantages of powerful segmental blockade of nociception, without the loss of other sensory modalities such as touch sensation, motor power or autonomic nervous system function. As with any new method of pain control, however, it has various side effects. Among them, respiratory depression is a potentially life- threatening complication which has been the limiting factor for the wide clinical application of this technique. This proposal is aimed at eliminating or lessening the complications associated with intrathecal and epidural opioid analgesia. The hypothesis to be tested is that the application of multiple receptor concepts will decrease the dose of opioid analgesics, thereby lessening or eliminating the complications mentioned above. Specific questions to be asked in this proposal will be: 1) What is the best adrenergic and/or serotonergic drugs, when applied directly on the spinal cord, which suppress the nociceptive single neuronal activities of wide dynamic range (WDR) neurons located in the dorsal horn of feline lumbar spinal cord? 2) Is there any synergism between the effects of adrenergic and/or serotonergic drugs and various opioid agonists (mu, kappa and delta) in suppressing the activities of WDR neurons? 3) What is the best combination of the drugs mentioned above to suppress the activities of WDR neurons with minimum activation of opiate receptors? The results of this portion of the acute animal experiment utilizing the sensitive screening method of neurophysiological study will determine the best combination of the adrenergic, serotonergic, and opioid agonists to suppress the nociceptive spinal neurons with minimal activation of opiate receptors. The next phase of experiments is to 4) conduct behavior analgesic studies in animals and simultaneously to 5) conduct toxicology studies. Following these preclinical studies, the last part of the specific aims is 6) a determination in human subjects of the analgesic effectiveness of the drug combinations identified in the animal experimentations.